Although a variety of neuropathological studies on pain have been actively conducted and pain treatment methods have been extensively studied, pain treatment still mostly depends upon use of narcotic analgesics already developed in the art.
Currently developed pain relievers affect peripheral or central nerves to decrease pain, and may typically include non-steroidal anti-inflammatory drugs (NSAID), COX-2 inhibitors, opiates and morphinomimetics, flupirtin, etc.
Representative examples of NSAID are paracetamol, and acetaminophen, which are presumed to affect the central nervous system and to inhibit cyclooxygenase, thus suppressing production of prostaglandin, and therefore, are known to reduce inflammation as well as pain. In particular, paracetamol shows fewer side effects and is relatively safe, however, when administered in doses higher than recommended, has a problem of inducing potentially fatal damage to the liver. Especially, NSAIDs drugs entail side effects such as paracusis, allergies, vision defects, gastritis, etc., in addition to the above problem.
Meanwhile, COX-2 inhibitor is a substance targeting COX-2 of cyclooxygenase, which is known as a target of NSAIDs and has COX-1 and COX-2, wherein COX-2 is known to influence pain. Rofecoxib (Vioxx) and celecoxib are representative of the COX-2 inhibitor as described above. Compared to NSAIDs, the COX-2 inhibitor exhibits substantially the same pain relieving effect while having reduced side effects, however, may cause heart and cerebrovascular disorders. For this reason, rofecoxib has been prohibited from being commercially available in the market, and is still a controversial matter in view of safety.
Opiates and morphinomimetics may typically include; archetypal opioid, codeine, oxycodone, hydrocodone, dihydromorphine, pethidine, and so forth. These drugs generally affect opioid receptors in the cerebrum to express a pain relieving effect. Tramadol is a drug based on the above substance but is more similar to venlafaxine rather than codeine, in terms of structure. However, in addition to activity with respect to the opioid receptor, the above drug also has a feature of effectively inhibiting reuptake of serotonin and norepinephrine. Although the above substance-based drugs have excellent pain relieving effects, these may induce vomiting, pruritus and constipation after administration and, in case of over-dosing, side effects such as confusion, respiratory depression, spasms, etc. may be a concern.
Flupirtin is a K+ channel opener having specific activity as an NMDA antagonist and is known as a drug without toxicity. Further, amitriptyline, nefopam, carbamazepine, gabapentin and pregabalin are typically used, however, some drugs are still not clearly understood in terms of functional mechanisms thereof. Further, since targets of the above drugs relate to the nervous system, these drugs may also be used as a remedy for curing further symptoms such as epilepsy, insomnia, post-traumatic stress disorder (PTSD), depression, nocturnal enuresis, stroke, etc., other than pain relief. A number of side effects possibly induced by corresponding drugs including, for example; hypotension, stroke, visual degradation, drowsiness, muscle stiffness, change in appetite, change in weight, or the like, have been reported in the art.
Accordingly, there is a significant need to develop novel medicaments capable of solving different problems such as side effects and toxicity of conventional pain relievers and relieving symptoms specific to pains.
Although a molecular-biological mechanism of pain and functions of drug targets based on the above mechanism have been relatively clearly disclosed, there is still considerable lack of understanding about a mechanism which results in pruritus (itching). With regard to a mechanism which leads to pain and itching in various peripheral tissues and spinal cords, significantly similar aspects are observed. However, most of pain therapeutics do not have an affect on pruritus, and narcotic analgesics are known to even cause pruritus.
Accordingly, in order to develop a drug capable of curing pruritus while relieving pain, it is necessary to more preferably understand differences between these two mechanisms, i.e., between physiological and pharmacological mechanisms. Of course, according to some examples of conventional art, gabapentin, which is one of neuropathic pain therapeutics widely used in the art, has been applied for treatment of neuropathic pruritus, i.e., pruritus of unknown origin, and successfully cured the same (M. A. Rose & P. C. A. Kam, Anaesthesia, 57:451, 2002; Yesudian P D & Wilson N J, Arch. Dermatol., 141(12):1507, 2005). However, neuropathic pruritus is a symptom caused by a disorder of the central nervous system and has a principal difference from typical itching.
Further, a cause of atopic dermatitis outbreak is unclear and it is known that genetic, environmental and immunological factors may be involved in the above disease. Since most of currently used atopic therapeutics are used only for relieving symptoms of the disease, there is still a strong need to develop a substantially essential and innovative therapeutic product. Developing a drug that can inhibit an initial itching stage and cure symptoms thereof, thus preventing skin damage or inflammation after a scratching stage, may be a basic treatment method of atopic dermatitis.
Meanwhile, a number of pain therapeutics have been developed in a form of an antagonist of a transient receptor potential vanilloid receptor 1 (TRPV1, ‘VR-1’). However, since the above products exhibited no efficacy or had clinically significant toxicity such as an increase in body temperature, most of research and development thereof have ended in failure. (ClinicalTrials.gov ID: NCT00878501; Gavva, N. R. et al. (2008) Pharmacological blockade of the vanilloid receptor TRPV1 elicits marked hyperthermia in humans. Pain 136, 202-210; Lehto, S. G. et al. (2008) Antihyperalgesic effects of (R,E)-N-(2-hydroxy-2,3-dihydro-1H-inden-4-yl)-3-(2-(piperidin-1-yl)-4-(trifluoromethyl)phenyl)-acrylamide (AMG8562), a novel transient receptor potential vanilloid type 1 modulator that does not cause hyperthermia in rats. J. Pharmacol. Exp. Ther. 326, 218-229). Further, even for a target of other pain therapeutics, i.e., CB2 or NK1, similar results were obtained and met with ill success. (Hill, R. (2000) NK1 (substance P) receptor antagonists—why are they not analgesic in humans? Trends Pharmacol. Sci. 21, 244-246; Rahn, E. J. and Hohmann, A. G. (2009) Cannabinoids as pharmacotherapies for neuropathic pain: from the bench to the bedside. Neurotherapeutics 6, 713-737). As such, major reasons of the failure in the development of pain therapeutics without desired efficacy are because individual targets may take a share of the pain mechanism but never comprise a whole part of the same. Therefore, it is suggested that only a drug simultaneously functioning on several targets may thoroughly control an overall pain mechanism. (Pang et al., A series of case studies: practical methodology for identifying antinociceptive multi-target drugs, 2012, Drug Discovery Today, vol 17, 425-434).
GlyT2 (Glycine transporter type 2) is an electrogenic carrier participating in Na+/Cl− ion transportation and primarily distributed around the spinal cord where pain arises, to thus play an important role in transferring a pain signal in the spinal cord. This fact is already widely known in the art.
5HT2A is a receptor relating to transfer of the pain signal, which is distributed in primary sensory neurons and spinal neurons and known to participate in peripheral/central sensitization of both the spinal cord neuron and peripheral nociceptor.
Accordingly, as a result of intensive effort to develop pain therapeutics affecting multiple targets, the present inventors found that a novel benzamide derivative and pharmaceutically acceptable salt thereof according to the present invention act not only as a GlyT2 antagonist but also a 5HT2A antagonist, which in turn, derives synergistic effects of activities of two targets, to exhibit excellent efficacy in prevention or treatment of pruritus, thereby completing the present invention.
The information as described in the above background art is only provided to more understand a background technology of the present invention, however, other information with respect to prior art well known to persons having ordinary skill in the art to which the present invention pertains, may not be included therein.